Antinociceptive Effect of P-Cymene and Cinnamaldehyde: Their Relationship with the L-Arginine-Nitric Oxide Pathway in Rats

Based on the previously known therapeutic properties of the active principles from essential plant oils, we investigated the antinociceptive effects of p-cymene (PC) and cinnamaldehyde (CNA) on carrageenan (CG)-induced inflammatory hyperalgesia in female Wistar rats, as well as their relationship with the L-arginine-nitric oxide pathway. Hyperalgesia was induced by intraplantar administration of CG (500 µg) into the rat hind paw, lasting 6 hours. The electronic von Frey apparatus measured the paw withdrawal threshold induced by pressure. Motor coordination in PC-treated animals was assessed using the Rota-rod test. PC and CNA (5, 25, 50 mg/kg BW), administered orally 50 minutes before CG, reduced CG-induced hyperalgesia, with PC showing a significantly dose-dependent (p<0.05, p<0.01, p<0.001) and stronger antinociceptive effect (p<0.001) than CNA. Compared to diclofenac (10 mg/kg), PC (50 mg/kg) demonstrated superior antinociceptive activity (p<0.001), while CNA (50 mg/kg) had a lower effect (p<0.05, p<0.01, p<0.001). Co-administration of PC (5 mg/kg) or CNA (5 mg/kg) with NOS inhibitors L-NAME (5 mg/kg) or AG (0.3 mg/kg) significantly enhanced the antinociceptive effect (p<0.01, p<0.001), with PC+L-NAME showing greater potentiation (p<0.001) than PC+AG. L-ARG (10 mg/kg), an NO donor, significantly reduced or reversed the antinociceptive effect of PC/CNA+NOS inhibitors (p<0.05, p<0.01, p<0.001). In the Rota-rod test, PC (100 mg/kg BW) did not impair motor coordination or cause CNS depression in female rats. Given their significant antinociceptive effects on CG-induced hyperalgesia, the close relationship between the L-arginine-NO system and their mechanism of action, and the fact that PC does not adversely affect the CNS, both PC and CNA are promising candidates for the development of new analgesic drugs in veterinary practice